DENGUE (V5)

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This book is dedicated to my loving wife, Tot,

whose support has made this book possible
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Contents

Contributors xiii

Preface xvii

Chapter 1 Dengue: Overview and History 1

Scott B. Halstead
Host Range 1
Geographical Distribution 3
Disease Burden and Cost 4
History 9

Chapter 2 The Infectious Agent 29

David W. C. Beasley and Alan D. T. Barrett
Classification 29
Virion Structure and Morphology 31
Immune Response Induced by Dengue Viruses 34
Proteins Encoded by the Virus 34
Replication Strategy 49
Conclusions 57

Chapter 3 Epidemiology 75
Scott B. Halstead
Introduction 75

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viii Contents

Ecology of Vector Mosquitoes 75

Infectious Disease Epidemiology of Aedes
aegypti–Borne Dengue 91
Sylvatic Cycle of Dengue Transmission 110

Chapter 4 Resistance to Infection 123

David W. Vaughn, LTC John M. Scherer
and Wellington Sun
Introduction 123
Innate Immunity 123
Antibody Responses in Natural Infection 127
Vaccine Development 132
Conclusion 149

Chapter 5 Clinical Features of Dengue 171

Jeremy Farrar
Introduction 171
Classification Schemes 172
Clinical Features 172
Differential Diagnosis 177
Specific Issues 178

Chapter 6 Management of Dengue 193

Bridget Wills
Introduction 193
Management 200
Conclusions 214

Chapter 7 Pathogenesis: Risk Factors Prior to Infection 219

Scott B. Halstead
Introduction 219
Host Factors 220
Viral Factors 240
Discussion 244
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Contents ix

Chapter 8 Elimination of Infection 257

Alan L. Rothman and Francis A. Ennis
Introduction 257
Innate and Adaptive Cellular Immune
Responses 257
Interferons 259
Natural Killer Cells 262
T Lymphocytes 263
Naturally Acquired versus Vaccine-Induced 273
Cellular Immunity
Summary 276

Chapter 9 Pathophysiology 285

Scott B. Halstead
Introduction 285
Dengue Infection Model 286
Immunopathogenesis 288
Models of Dengue Pathophysiology 306

Chapter 10 Diagnosis of Dengue Virus Infections 327

Timothy P. Endy, Ananda Nisalak
and David W. Vaughn
Introduction 327
Antibody and Virus Patterns in Dengue
Virus Infection 328
Diagnostic Pathway in Patients with Suspected
Acute Dengue 330
Serological Assays 331
Virus Isolation and Serotype Identification 343
Immunohistochemistry 346
Genome-Based Assays 347
Future Directions 349
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x Contents

Chapter 11 The Control of Dengue Vectors 361

Norman G. Gratz and Scott B. Halstead
Introduction 361
Existing Control Methods; Control of the
Aquatic Stages 363
The Environmental Control of Ae. aegypti
Larval Habitats 363
Larvicides Used for the Control of Ae. aegypti 367
The Biological Control of Ae. aegypti Larvae 369
The Use of Fish Predators Against Ae. aegypti
Larvae 369
Predaceous Mosquito Larvae for the Control
of Ae. aegypti 370
The Use of Copepod Predators 370
The Use of Bti 371
Conclusions on the Feasibility of Larval Control 372
Adulticidal Control of Ae. aegypti 373
Space Spray Adulticiding for Control
of Ae. aegypti; The Use of Thermal Fogs 374
Space Spray Adulticiding for Control
of Ae. aegypti; The Use of ULV 374
Conclusions: What Are the Options? 377

Chapter 12 Biological Control of Dengue Vectors: Promises

from the Past 389
Brian H. Kay

Chapter 13 Mosquito Control: Behavioral and

Community Interventions 407
Peter Winch, Elli Leontsini and Linda S. Lloyd
Conventional Approaches to Behavior Change
Interventions 408
The Emerging Paradigm for Behavioral
Interventions 411
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Contents xi

Role of the Community 416

Conclusions 418

Chapter 14 Controversies 425

Jose Rigau-Perez, Scott B. Halstead
and David M. Morens
I. The World Health Organization Definition of
Dengue Hemorrhagic Fever is Inadequate
for Clinical and Epidemiological Purposes 427
Pro: José G. Rigau-Pérez
Con: Scott B. Halstead 431
II. The Association Between Dengue Hemorrhagic
Fever and Second Dengue Infections is
Simply Coincidental 436
Pro: David M. Morens
Con: Scott B. Halstead 440
III. Dengue Hemorrhagic Fever is Caused by
Virulent Dengue Viruses 447
Pro: David M. Morens
Con: Scott B. Halstead 453
IV. Dengue Hemorrhagic Fever is Caused by
an Abnormal or Accelerated T Cell
Response to Infection 462
Pro: David M. Morens
Con: Scott B. Halstead 465
V. Dengue Hemorrhagic Fever is Caused by
Autoimmune Phenomena Triggered
by a Dengue Viral Infection 469
Pro: David M. Morens
Con: Scott B. Halstead 472

Index 475
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Contributors

Alan D. T. Barrett, PhD

Department of Pathology
University of Texas Medical Branch
301 University Blvd.
Galveston, TX 77555-0609, USA

David W. C. Beasley, PhD

Department of Microbiology and Immunology
University of Texas Medical Branch
301 University Blvd.
Galveston, TX 77555-0609, USA

Timothy P. Endy, MD, MPH

Associate Professor of Medicine
Chief, Infectious Disease Division
Department of Medicine
SUNY Upstate Medical University
725 Irving Avenue, Suite 304
Syracuse, NY 13210, USA

Francis A. Ennis, MD
Center for Infectious Disease and Vaccine Research
University of Massachusetts Medical School
55 Lake Avenue North, Room S6-862
Worcester, MA 01655, USA
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xiv Contributors

Jeremy Farrar, FRCP, FRCP (Ed), FmedSci, PhD, OBE

Director, Oxford University Clinical Research Unit
The Hospital for Tropical Diseases
190 Ben Ham Tu, Ho Chi Minh City, Viet Nam
Professor of Tropical Medicine
Oxford University
Professor of International Health
London School of Hygiene and Tropical Medicine

Norman G. Gratz
Formerly, Chief, Vector Borne Diseases Division
World Health Organization (WHO)
Avenue Appia 20, CH-1211
Geneva 27, Switzerland

Scott B. Halstead, MD
Director, Pediatric Dengue Vaccine Initiative (PDVI)
Supportive Research and Development Program
5824 Edson Lane, N. Bethesda, MD 20852, USA

Brian H. Kay, AM, PhD, FAA, FACTM

Deputy Director, Australian Centre for International
and Tropical Health and Nutrition (ACITHN)
Professor in Tropical Health
Queensland Institute of Medical Research
Post Office Royal Brisbane Hospital
Brisbane, QLD 4029, Australia

Elli Leontsini, MD, MPH

Associate, Social and Behavioral Interventions Program
Department of International Health
Johns Hopkins Bloomberg School of Public Health
615 North Wolfe Street, Room E5034
Baltimore, MD 21205-2103, USA
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Contributors xv

Linda S. Lloyd, DrPH

Public Health Consultant
3443 Whittier St.
San Diego, CA 92106, USA

Ananda Nisalak, MD
Department of Virology
Armed Forces Research Institute of Medical Sciences
USAMC-AFRIMS, APO, AP 96546, USA

Alan L. Rothman, MD
Center for Infectious Disease and Vaccine Research
University of Massachusetts Medical School
55 Lake Avenue North, Room S6-862
Worcester, MA 01655, USA

LTC John M. Scherer, PhD, MT (ASCP)

United States Army Research Institute of Infectious Diseases
1425 Porter Street
Fort Detrick, MD 21702, USA

Wellington Sun, MD
Chief, Dengue Branch
Division of Vector-Borne Infectious Diseases
Centers for Disease Control and Prevention
1324 Calle Canada, San Juan, Puerto Rico 00920

David W. Vaughn, MD, MPH, FAAP

Director, Global Clinical Research and Development
GlaxoSmithKline Biologicals, North America
2301 Renaissance Boulevard, Mail Code RN0220
King of Prussia, PA 19406-2772, USA
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xvi Contributors

Bridget Wills, MRCP, DM

Senior Clinical Research Fellow
Oxford University Clinical Research Unit
The Hospital for Tropical Diseases
190 Ben Ham Tu, Ho Chi Minh City, Viet Nam
Honorary Senior Lecturer/Consultant in Paediatric
Infectious Diseases, St. Mary’s Hospital
Imperial College Healthcare NHS Trust, London, UK

Peter Winch, MD, MPH

Associate Professor
Director, Social and Behavioral Interventions Program
Associate Chair, Department of International Health
Johns Hopkins Bloomberg School of Public Health
615 North Wolfe Street, Room E5030
Baltimore, MD 21205-2103, USA
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Preface

Dengue is an enormous problem. It is both local and global. In its behav-

ior, dengue most nearly resembles the intimate and ubiquitous respiratory
diseases that make life miserable for human beings on an equal opportu-
nity basis and whose treatments fill the pages of standard medical text-
books. In hundreds of millions of households on earth there lives a
stealthy insect. It is happy in its domesticity, rearing its generations on
human blood. Dengue, the commensal virus that this insect harbors, is
perfectly adapted to a generational cycle — man to mosquito to man. It
evolved from a common ancestor virus, no doubt one harbored by subhu-
man primates and transmitted by jungle mosquitoes. A period of isolation
and the accumulation of a succession of small mistakes in RNA tran-
scription resulted in the evolution of four distinct serotypes. Serial infec-
tion with one or more types is now the fate of perhaps 2.5 billion people
who live in tropical and subtropical countries. This book describes aspects
of the dengue story in a format designed for students at various levels. It
is not a comprehensive presentation of contemporary dengue research, but
rather a compact, accessible and authoritative description of major bio-
logical features in the complex story of dengue as a human disease.

Dengue: Overview and History. This chapter, written by the Editor,

reviews the history of the term dengue, the viruses associated with the
dengue syndrome and the history of dengue hemorrhagic fever. Statistics
are provided showing the impact of dengue in terms of morbidity, mortal-
ity and cost during the past 40 years.

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xviii Preface

The Infections Agent. This chapter, written by highly productive arbovi-

rologists Drs. David Beasley and Alan Barrett, University of Texas
Medical Branch, Galveston, describes the genetic and amino acid
sequences of the four dengue virus types and their genotypes, the struc-
ture of the entire virus and of key surface proteins. Descriptions are pro-
vided of the structure of gene products along with a summary of the
current understanding of mechanisms of entry of dengue into cells,
uncoating, transcription of RNA, translation of RNA, the composition and
function of specified proteins, and the respective contribution of viral and
host enzymes and replicative machinery to viral replication.

Epidemiology. In this authoritative chapter, the Editor describes the bio-

nomics of dengue mosquito vectors together with many of the elements
that contribute to influencing the transmission of dengue viruses, includ-
ing the mosquito, factors in the environment and the complex controls
contributed by the host.

Resistance to Infection. US Army physicians, led by Dr. David Vaughn,

who spent more than two decades conducting research on dengue vac-
cines, have written this chapter. They summarize knowledge of the anti-
body responses to dengue infection and the role of antibodies in protection
against dengue infections. The current status of dengue vaccine develop-
ment is reviewed.

Clinical Features of Dengue. Written by Dr. Jeremy Farrar, Director,

Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam,
this chapter describes the signs and symptoms of mild and severe dengue
diseases, including unusual manifestations.

Treatment. Principles and details of treating children and adults with mild
and severe dengue syndromes are given by Dr. Bridget Wills, an acknowl-
edged world authority who conducts clinical research on dengue illnesses
at the Oxford Clinical Research Unit, Ho Chi Minh City, Vietnam.

Pathogenesis. This is the beginning of the story of severe dengue disease.

The Editor describes the role that dengue antibodies play in governing the
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Preface xix

outcome of infection by neutralizing or enhancing dengue virus infec-

tions, providing controls for the major afferent mechanism that governs
the intensity of dengue infections and the severity of dengue diseases.

Elimination of Infection. This chapter, by Dr. Alan Rothman, Professor of

Medicine, University of Massachusetts Medical Center, a world authority
on immune responses to dengue infection, summarizes the rich contem-
porary research experience on the cellular immune response to dengue
virus infection. Emphasis is on the kinetics and specificity of the cell-
mediated responses to dengue infection and the role these play in elimi-
nation of dengue-virus-infected cells and in producing the
pathophysiological changes of dengue diseases.

Pathophysiology. The Editor describes how and when immunological

responses to dengue infections generate chemokine and cytokine
responses. Evidence concerning the role that cytokines play in the patho-
physiological responses to dengue infection is presented and discussed.
New findings that provide amazing insights into the compelling story of
antibody-dependent enhancement of dengue infection are presented.

Diagnosis. Diagnosis of recent primary or secondary dengue and other

flavivirus infections is presented. Included are serological methods, virus
isolation, detection of viral antigen by various methods, and the use of
PCR and molecular probes to detect and quantitate viral nucleic acid in
blood or infected tissues. This chapter has been written by Prof. Timothy
Endy along with dengue virologists who served as virologists at the
Armed Forces Research Institute of the Medical Sciences in Bangkok,
Thailand, and at the Walter Reed Army Institute of Research,
Washington, D.C.

Mosquito Control. Control of mosquito vectors is covered in three chap-

ters. Chapter 11 provides a seminar on classical methods of the control of
dengue vector mosquitoes. It has been written by an authority with a spe-
cialist experience or perspective — the late Dr. Normal Gratz, Chief of
Vector Control, World Health Organization. This chapter assesses the
strengths and weaknesses of contemporary vector control, including the
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xx Preface

proper and improper use of insecticides and other mechanical or chemical

antilarval methods. In Chap. 12, Dr. Brian Kay, Director, Entomology,
Queensland Institute of Medical Research, Brisbane, Australia, a world
authority, discusses biological control of mosquito larvae. And in Chap. 13,
Drs. Peter Winch and Elie Leontsini, Associate Professors, Department of
International Health, Johns Hopkins School of Hygiene and Public Health,
review methods for community-based programs to effect the control of
dengue mosquito vectors.

Controversies. Unique to this series are discussions on major controver-

sies in dengue pathogenesis and diagnosis. Dr. Jose Rigau-Perez, formerly
with the CDC Dengue Laboratory in Puerto Rico, critiques the usefulness
of the current WHO case definition of dengue hemorrhagic fever as an
epidemiological and clinical management tool, with rebuttal by the Editor.
David Morens, Assistant to the Director, NIAID, NIH, and the Editor
present and discuss the pros and cons, respectively, of four major contro-
versies relating to the causation of severe dengue disease.

Acknowledgements. Many thanks to Lizzie Bennett of Imperial College

Press, London and Joy Quek of World Scientific Publishing Company,
Singapore for their assistance in preparing, revising and tracking the sub-
mission of manuscripts. The Editor wishes to thank the contributors to this
book, who remained faithful despite an editing process that consumed
much of a decade. The months that the Editor has spent traveling the
world to learn about dengue and the lonely hours spent writing and rewriting
the dengue story have exacted a price in abandonment and missed social
occasions, the brunt being borne by his lovely and tolerant wife. He owes
her debts far beyond repayment.